Immunoconjugates are developed as highly potent and specific agents for the treatment of cancer and other conditions. An immunoconjugate is composed of an antibody specifically recognizing a target cell antigen, such as a tumor cell antigen, and one or several covalently linked molecules of a drug, particularly a cytotoxic drug such as a maytansinoid, a taxane, or a CC-1065 analog. Another name used for such immunoconjugates is antibody-drug conjugates. Immunoconjugates are inactive during circulation but bind to target cell surfaces, whereupon they are internalized by the cells. By mechanisms not yet fully understood, the drugs are subsequently released from the antibody and can exert their pharmacological effect.
The targeted delivery of cytotoxic drugs to target cells, such as cells making up cancer tissue, potentially improves the therapeutic indexes of the cytotoxic drugs. Typically, cytotoxic drugs used as immunoconjugates are 100 to 1000-fold more potent than conventional chemotherapy drugs. Examples of such immunoconjugates are disclosed in International (PCT) Patent Application Nos. WO 00/02587, 02/060955, and 02/092127; U.S. Pat. Nos. 5,475,092, 6,340,701, 6,171,586, 6,706,708 B2, and 6,756,397 B2; and Chari et al., Cancer Res., 52, 127-131 (1992).
Pharmaceutical compounds such as immunoconjugates are generally combined with one or more pharmaceutically acceptable carriers, excipients, and/or stabilizers to provide a pharmaceutical composition that allows for administration to patients and for storage and transport of the pharmaceutical compound. Like other protein pharmaceuticals, immunoconjugates are prone to degradation such as oxidation, deamidation, as well as particle and aggregate formation, etc. (Manning et al., Pharm. Res. 6, 903-918 (1989); Ahern and Manning, Stability of Protein Pharmaceuticals: Part A, Chemical and Physical pathways of Protein Degradation, Plenum, New York, (1992); and Cleland et al., Crit. Rev. Ther. Drug Carrier Syst. 10, 307-377 (1993)).
Particle formation in protein pharmaceuticals, in particular, can destabilize the pharmaceutical compound, thus making the formulation less potent or even harmful for clinical use. For example, particles in injected pharmaceutical formulations can cause significant injury to veins or prolonged venous stasis in patients. In addition, aggregate formation is a major degradation pathway of protein pharmaceuticals (Chari et al., Pharm Res. 20, 1325-1336 (2003)), and may lead to undesirable effects such as immunogenicity.
The conjugation of drugs, especially cytotoxic drugs, which are often hydrophobic, small molecules, to hydrophilic monoclonal antibodies, introduces additional instability to immunoconjugates. Addressing the properties attributable to the antibody component of immunoconjugates is critical to the generation of stable liquid or lyophilized pharmaceutical formulations. To this end, WO 2004/004639 A2 and U.S. Patent Application No. 2004/0,241,174 A1 describe compositions of immunoconjugates. However, these compositions do not adequately address particle and aggregate formation in pharmaceutical compositions of immunoconjugates.
Thus, there remains a need for pharmaceutical compositions of immunoconjugates that are substantially free of particles and/or aggregates, and remain substantially free of particles and/or aggregates during storage and transport.
The present invention provides pharmaceutical compositions of immunoconjugates that are substantially free of particles and/or aggregates and prevent the formation of particles and/or aggregates during storage and/or transport. Methods for use of the pharmaceutical compositions are also provided. These and other advantages of the invention, as well as additional inventive features, will be apparent from the descriptions of the invention provided herein.